This application represents the efforts of a multidisciplinary group at the University of North Carolina at Chapel Hill (Depts. of Medicine, Biochemistry/Biophysics, and the CF and Environmental Medicine, Asthma, and Lung Biology Centers) led by R.C. Boucher, P.I. Dr. Boucher is a senior investigator who was originally trained in COPD (Drs. N. Anthonisen/J. Hogg, mentors) and, after a long interval studying genetic causes of bronchitis, proposes to apply principles generated from these studies to the pathogenesis of COPD acute exacerbations (AEs). We hypothesize that 1) a COPD AE reflects a transient worsening/failure of a major human airway defense system, i.e., the mucus (ciliary/cough-dependent) clearance mechanism; 2) the COPD patient is vulnerable to triggers of AEs because mucus clearance is chronically compromised by cigarette smoke-induced inflammation/damage; and 3) respiratory viruses trigger many COPD AEs via direct infection of the lower airway epithelium and derange the epithelial ion transport regulatory systems (e.g., extracellular ATP/adenosine and cytokines) that coordinate salt/water transport and mucin secretion rates. The net effect is to disturb in an AE the relative mucus hydration (% solids) required for efficient mucus clearance. This scenario produces during an AE slowing/collapse of ciliary and cough-dependent mucus clearance, airways obstruction, worsening of bacterial infection in colonized patients, and ultimately dyspnea. Finally, we hypothesize that we do little to acutely downregulate mucin secretion. However, we predict that we can rehydrate the abnormal mucus characteristic of an AE via inhalation of hypertonic saline (HS) and this maneuver will be safe in the COPD patient with an AE. We will test these hypotheses in two parallel longitudinal studies that will 1) explore the effects of an AE on mucus clearance, and the mechanisms that account for slowed clearance; and 2) explore the safety and efficacy of HS in restoring mucus clearance during an AE. The approaches to testing these hypotheses/aims include: 1) in vivo measurements of ciliary and cough-dependent mucus clearance; 2) in vitro measurements of mucus biochemical and biophysical properties; 3) measurements of airway nucleotide/nucleoside levels and metabolic paths. The ultimate goals for the U.S. COPD patient population are to generate a mechanistic understanding of a major component of an AE and provide the mechanistic basis for novel therapies of AEs.